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Multistage Delivery of Active Agents 111111111111111111111111111111111111111111111111111111111111111111111111111111 (12) United States Patent (io) Patent No.: US 10,143,658 B2 Ferrari et al. (45) Date of Patent: Dec. 4, 2018 (54) MULTISTAGE DELIVERY OF ACTIVE 6,355,270 B1 * 3/2002 Ferrari ................. A61K 9/0097 AGENTS 424/185.1 6,395,302 B1 * 5/2002 Hennink et al........ A61K 9/127 (71) Applicants:Board of Regents of the University of 264/4.1 2003/0059386 Al* 3/2003 Sumian ................ A61K 8/0241 Texas System, Austin, TX (US); The 424/70.1 Ohio State University Research 2003/0114366 Al* 6/2003 Martin ................. A61K 9/0097 Foundation, Columbus, OH (US) 424/489 2005/0178287 Al* 8/2005 Anderson ............ A61K 8/0241 (72) Inventors: Mauro Ferrari, Houston, TX (US); 106/31.03 Ennio Tasciotti, Houston, TX (US); 2008/0280140 Al 11/2008 Ferrari et al. Jason Sakamoto, Houston, TX (US) FOREIGN PATENT DOCUMENTS (73) Assignees: Board of Regents of the University of EP 855179 7/1998 Texas System, Austin, TX (US); The WO WO 2007/120248 10/2007 Ohio State University Research WO WO 2008/054874 5/2008 Foundation, Columbus, OH (US) WO WO 2008054874 A2 * 5/2008 ............... A61K 8/11 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. Akerman et al., "Nanocrystal targeting in vivo," Proc. Nad. Acad. Sci. USA, Oct. 1, 2002, 99(20):12617-12621. (21) Appl. No.: 14/725,570 Alley et al., "Feasibility of Drug Screening with Panels of Human tumor Cell Lines Using a Microculture Tetrazolium Assay," Cancer (22) Filed: May 29, 2015 Research, Feb. 1, 1988, 48:589-601. Becker et al., "Peptide-polymer bioconjugates: hybrid block copo- lymers generated via living radical polymerizations from resin- (65) Prior Publication Data supported peptides," Chem. 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Charnay et al., "Reduced Symmetry Metallodielectric Nanoparticles: Chemical Synthesis and Plasmonic Properties," J. Phys. Chem. B, (51) Int. Cl. 2003, 107:7327-7333. A61K 9/127 (2006.01) Chen et al. "Soluble ultra-short single-walled carbon nanotubes," J. A61K 9/50 (2006.01) Am. Chem. Soc., 2006, 128:10568-10571. A61K 9/51 (2006.01) Cheng et al. "Nanotechnologies for biomolecular detection and A61K 31/165 (2006.01) medical diagnostics," Curr. Opin. Chem. Biol., 2006, 10:11-19. Chiapponi et al., "Tailored porous silicon microparticles: fabrication A61K 31/704 (2006.01) and properties", Chemphyschem., Apr. 6, 2010, v. 11, No. 5, pp. A61K 31/7088 (2006.01) 1029-1035. (52) U.S. Cl. Ciardiello et al., "A novel approach in the treatment of cancer: CPC ................ A61K 9/50 (2013.01); A61K 9/127 targeting the epidermal growth factor receptor," Clin. Cancer Res., (2013.01); A61K 9/1271 (2013.01); A61K 9/51 Oct. 2001, 7:2958-2670. (2013.01); A61K 31/165 (2013.01); A61K (Continued) 31/704 (2013.01); A61K 31/7088 (2013.01) Primary Examiner Janet L Epps-Smith (58) Field of Classification Search (74) Attorney, Agent, or Firm Winstead PC CPC ................ A61K 31/165; A61K 31/704; A61K (57) ABSTRACT 31/7088; A61K 9/127; A61K 9/1271; A61K 9/50; A61K 9/51; A61K 424/45; Multistage delivery vehicles are disclosed which include a A61K 424/489; A61K 514/34; A61K first stage particle and a second stage particle. The first stage 514/44 particle is a micro or nanoparticle that contains the second USPC .......................... 514/34, 44 A; 424/450, 489 stage particle. The second stage particle includes an active See application file for complete search history. agent, such as a therapeutic agent or an imaging agent. The multistage delivery vehicle allows sequential overcoming or (56) References Cited bypassing of biological barriers. The multistage delivery vehicle is administered as a part of a composition that U.S. PATENT DOCUMENTS includes a plurality of the vehicles. Methods of making the multistage delivery vehicles are also provided. 6,099,864 A 8/2000 Morrison et al. 6,107,102 A 8/2000 Ferrari 28 Claims, 58 Drawing Sheets US 10,143,658 B2 Page 2 (56) References Cited Kerbel et al., "Antiangiogenic Therapy: AUniversal Chemosensitiza- tion Strategy for Cancer?" Science, May 26, 2006, 312:1171-1175. Kim et al. "Near-infrared fluorescent type II quantum dots for OTHER PUBLICATIONS sentinel lymph node mapping," Nat. Biotechnol., Jan. 2004, 22(1 ): 93-97. Cloninger M.J., "Biological applications of dendrimers," Curr. Lan et al., "Surface modification of silicon and gold-patterned Opin. Chem. Biol., 2002, 6:742-748. silicon surfaces for improved biocompatibility and cell patterning Cohen et al., "Microfabrication of Silicon-Based Nanoporous Par- selectivity," Biosens. 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